Hepatitis B virus (HBV) causes a significant global health burden with an estimated 360 million people persistently infected and 500,000-700,000 deaths annually from HBV-associated liver disease. Five percent of adults and ninety-five percent of neonates exposed to the virus become persistently infected. Persistent infection with HBV leads to liver cirrhosis and hepatocellular carcinoma, which has a five-year survival rate of only 9%. Therapeutics such as nucleoside analogs are effective at clearing the infection in approximately 20-30% of treated patients; however, resistance to nucleoside analogs is an increasing problem, with 70% of patients becoming resistant to lamivudine and 18% becoming resistant to adefovir and tenofovir after four years of treatment.
HBV is a member of the Hepadnaviridae family and has a small double-stranded DNA genome of approximately 3,200 base pairs and a strict tropism for hepatocytes. A model virus for HBV is the duck hepatitis B virus (DHBV), which has a comparable tropism for avian hepatocytes, and a common viral structure, life cycle and genome. Upon infection, the viral genome is converted from a relaxed circular form to a covalently closed circular (cccDNA) form in the nucleus of hepatocytes. This cccDNA form associates with several proteins to form a ‘mini-chromosome’ structure. and is the reservoir from which transcription of viral genes and progeny genomes occur. It is highly stable with 3-50 copies per nucleus and a half-life of approximately fifty days. Thus, when treatment with nucleoside analogs is stopped in infected patients, the cccDNA reservoir can result in a resurgence of viral production. There are currently no therapeutics available which target the cccDNA of HBV.
There remains a need for treatment options for individuals persistently infected with HBV.